Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin

ABSTRACT

The invention relates to liquid pharmaceutical formulations for oral administration with the modified release of amoxicillin, said formulations consisting of suspensions of coated particles of amoxicillin (microcapsules). According to the invention, the microcapsules constituting the disperse phase of the suspension are designed to allow the modified release of the amoxicillin according to a profile that does not change during the storage of the liquid suspension. To do this the inventors propose the selection of a specific coating composition for the microcapsules which consists of at least four components that allow these microcapsules to be stored in water without modifying their properties of modified release of the amoxicillin, this liquid phase furthermore being saturated with amoxicillin.

The invention relates to the field of the modified release ofpharmaceutical active principles. In the present disclosure, theexpression “modified release” arbitrarily denotes release of the activeprinciple(s) which starts as soon as the galenical form is brought intocontact with its dissolution medium (in vivo or in vitro) or release ofthe active principle(s) which does not start until after a predeterminedperiod ranging e.g. from 0.5 to several hours. In terms of theinvention, the time taken to release 50% of the active principle(s) istypically several hours and can extend e.g. from 0.5 to 30 hours.

More precisely, the invention relates to liquid pharmaceuticalformulations for oral administration with the modified release ofamoxicillin (an antibiotic of the β-lactam family). These formulationsconsist of suspensions or dispersions of microcapsules, each of which isformed of a core comprising amoxicillin and of a coating enveloping saidcore. According to the invention, the microcapsules constituting thedisperse phase of the suspension are designed to allow the modifiedrelease of the amoxicillin.

The invention further relates to dry pharmaceutical formulations for usein aqueous suspensions reconstituted at the beginning of the treatment.These reconstituted aqueous suspensions are stable throughout thetreatment and allow the modified release of the amoxicillin.

These suspensions are of particular value for

-   -   increasing the interval between two dosage units, for example        every 12 hours instead of every 8 hours;    -   and facilitating the oral administration of an amoxicillin-based        drug. In fact, a large number of patients would rather drink a        liquid medicinal suspension than swallow one or more tablets.        Compliance is thereby improved. This is of most particular value        to populations incapable of swallowing tablets that are often        large, namely infants, children and the elderly;    -   while at the same time improving the taste of the suspension.

The invention further relates to a specific process for the preparationof microcapsules of amoxicillin to be suspended in water.

Numerous types of microcapsules in dry form are known. In particular,patent EP-B-0709 087 describes a (pharmaceutical or dietetic) galenicalsystem, preferably in the form of a tablet, advantageously adisintegrating tablet, or in the form of a powder or gelatin capsule,characterized in that it comprises microcapsules of the reservoir typecontaining at least one medicinal and/or nutritional active principle(AP) selected especially from antibiotics, and intended for oraladministration, characterized in that:

-   -   they consist of particles of AP each covered with a film coating        of the following composition:        -   1—at least one film-forming polymer (P1) insoluble in the            tract fluids, present in an amount of 50 to 90% by dry            weight, based on the total weight of the coating            composition, and consisting of at least one water-insoluble            cellulose derivative, ethyl cellulose and/or cellulose            acetate being particularly preferred;        -   2—at least one nitrogen-containing polymer (P2) present in            an amount of 2 to 25% by dry weight, based on the total            weight of the coating composition, and consisting of at            least one polyacrylamide and/or poly-N-vinylamide and/or            poly-N-vinyllactam, polyacrylamide and/or            polyvinylpyrrolidone being particularly preferred;        -   3—at least one plasticizer present in an amount of 2 to 20%            by dry weight, based on the total weight of the coating            composition, and consisting of at least one of the following            compounds: glycerol esters, phthalates, citrates, sebacates,            cetyl alcohol esters, castor oil, salicylic acid and cutin,            castor oil being particularly preferred;        -   4—and at least one surfactant and/or lubricant present in an            amount of 2 to 20% by dry weight, based on the total weight            of the coating composition, and selected from anionic            surfactants, preferably alkali metal or alkaline earth metal            salts of fatty acids, stearic and/or oleic acid being            preferred, and/or from non-ionic surfactants, preferably            polyethoxylated sorbitan esters and/or polyethoxylated            castor oil derivatives, and/or from lubricants such as            stearates, preferably calcium, magnesium, aluminium or zinc            stearate, or stearylfumarate, preferably sodium            stearylfumarate, and/or glycerol behenate, it being possible            for said agent to comprise only one or a mixture of the            above-mentioned products;    -   they have a particle size of between 50 and 1000 microns;    -   and they are designed so as to be able to reside in the small        intestine for a period of at least about 5 hours, thereby        allowing the absorption of the AP during at least part of their        residence time in the small intestine.

Said document relates only to dry pharmaceutical forms based onmicrocapsules and makes no mention of oral liquid pharmaceutical formsbased on microcapsules.

Oral pharmaceutical formulations for the modified release of amoxicillincurrently exist only in the form of tablets. Patents WO-A-94/27557,WO-A-95/20946, WO-A-95/28148, WO-A-96/04908, WO-A-00/61115,WO-A-00/61116, WO-A-01/47499 and WO-A-02/30392 describe differentformulations of such tablets. These tablets are large, such as thetablet of Example 1 of patent WO 02/30392, which has a total weight of1600 mg for a dose of 1000 g. These tablets cannot be administered topatients with swallowing difficulties, and even less to children orinfants, who in any case are incapable of swallowing them and for whom,in addition, the dose administered has to be adapted according to theirweight.

For such applications, multidose suspensions or solutions are preferableto tablets as pharmaceutical forms.

Pharmaceutical suspensions or solutions of amoxicillin exist to meetthis need. Examples of these are the formulations described by patentapplication WO-A-98/35672 or WO-A-98/35672. Efforts to improve thesesuspensions have been directed towards suspension stability (patentapplication WO-A-00/50036), gastrointestinal tolerance (patentapplications WO-A-97/06798 & WO-A-00/03695) or taste improvement (patentapplication WO-A-98/36732).

However, none of these known suspensions allows the modified release ofamoxicillin, which is necessary to increase the duration of action ofthe amoxicillin and treat certain indications such as pneumonia causedby resistant streptococci. To meet this need, a formulation containingmore than the customary amount of amoxicillin is described in patentapplication WO-A-97/09042, in which the amoxicillin is in animmediate-release form.

Liquid suspensions for the modified release of amoxicillin are difficultto produce. The main difficulty to be overcome is that of avoiding therelease of the amoxicillin into the liquid phase during storage of thesuspension, while allowing modified release as soon as it enters thegastrointestinal tract. This objective is particularly difficult toachieve because the amoxicillin is stored in a liquid for a very longtime (the duration of the treatment, i.e. about ten days) compared withthe desired release time in the gastrointestinal tract fluids (a fewhours, at most 12). Furthermore, its prolonged residence in the liquidphase during storage must not perturb the modified-release system to thepoint of degrading the release profile and release time of theamoxicillin.

Furthermore, for these liquid formulations to be fully effective, it isknown to be important that:

-   -   the microcapsules are very small (<1000 microns),    -   and the weight fraction of coating excipients is limited, this        modality being all the more difficult to achieve because, due to        their small size, the microcapsules have a large specific        surface area, accelerating the release.

As regards the prior art concerning oral liquid pharmaceutical forms forthe modified release of active principles, PCT patent applicationWO-A-87/07833 and U.S. Pat. No. 4,902,513 should be mentioned first ofall; . . . disclose aqueous suspensions of microcapsules of activeprinciple (e.g. theophylline) with modified release of the activeprinciple (e.g. 12 h). These suspensions are prepared by saturating theaqueous phase with the active principle before incorporating themicrocapsules of active principle into this aqueous phase. Thecomposition of the coating agent for the microcapsules that allows themodified release of the active principle is not described in saiddocuments. Now, this coating composition is a decisive factor inguaranteeing the maintenance of the modified-release profile of themicrocapsules after storage in the aqueous phase. The technical proposaldescribed appears not to disclose the means of solving the dual problemof producing a liquid suspension of a modified-release microcapsularform without interfering with the stability of the modified-releaseprofile of the active principle after the microcapsules have been storedin the liquid phase.

European patent application EP-A-0 601 508 relates to an aqueoussuspension for the oral administration of naxopren according to amodified-release profile. This suspension comprises coated microgranulesof naxopren suspended in a syrupy aqueous liquid phase. The technicalproblem underlying this invention is to provide a modified-release formof naxopren containing a 1000 mg dose and capable of administration in asingle daily dosage unit.

The microgranules consist of naxopren, polyvinylpyrrolidone and lactose(90-300 μm). Their coating is made up of 4 layers. The first comprisesdiethyl cellulose/diethyl phthalate/polyethylene glycol. The second isbased on EUDRAGIT® (meth)acrylate/(meth)acrylic copolymers. The thirdcomprises glycerol stearate/wax/fatty alcohols and the fourth consistsof an enteric covering based on cellulose acetate/phthalate. Thenaxopren undergoes modified release over 24 hours.

Example 22 of said European patent application EP-A-0 601 508 contains ademonstration of the stability of the release profile after 30 days'storage of the liquid suspension.

One of the disadvantages of this suspension derives from the entericlayer, which prohibits the use of a suspension of neutral pH becausethis layer is designed to disintegrate and become liquid at neutral pH.Another disadvantage of this enteric layer is that it blocks the releaseof the active principle in the stomach at acidic pH. Now, amoxicillin,whose absorption window is situated in the upper parts of thegastrointestinal tract, must be released as soon as it reaches thestomach in order to be effectively absorbed. Furthermore, thismultilayer solution to the problem is very complex and in additionspecific to naproxen.

PCT patent application WO-A-96/01628 discloses a liquid pharmaceuticalformulation for the oral administration, according to a modified-releaseprofile (12 hours), of an active principle consisting of moguisteine.The object is to propose a modified-release liquid formulation ofmoguisteine which is easy to measure out and ingest, has a release timethat makes it possible to avoid multiple dosage units, is stable overtime in aqueous suspension and is pleasantly flavoured in order tofavour compliance, and whose manufacture does not involve the use oftoxic substances like solvents. To achieve this object, the inventionaccording to PCT patent application WO-A-96/01628 proposes a suspension,in a weakly hydrated liquid phase (essentially based on sorbitol andglycerol), of microgranules (90-300 μm) of moguisteine coated with afirst, hydrophilic layer consisting of cellulose acetate/phthalate anddiethyl phthalate, a second, hydrophobic layer containing glycerolstearate/wax/fatty alcohols, and a third, hydrophilic layer identical tothe first.

This multilayer form is very complex to prepare and in addition isspecific to moguisteine.

In this state of the art, the essential objective of the presentinvention is to propose an aqueous suspension, or a preparation for anaqueous suspension, of microcapsules of amoxicillin for the oraladministration of amoxicillin according to a modified-release profile,in which the coating of the microcapsules is designed in such a way thatthe release profile is not perturbed and does not depend on themaceration time of the microcapsules in the liquid (preferably aqueous)phase. Thus the amoxicillin contained in the microcapsules would beprevented from escaping into the liquid phase throughout the storage ofthe suspension, but a modified release of the amoxicillin would beallowed as soon as it entered an environment suitable for triggering therelease, namely in vivo in the gastrointestinal tract and in vitro underthe conditions of a dissolution test performed just after suspension ofthe microcapsules in the solvent (preferably aqueous) phase, using atype II apparatus according to the European Pharmacopoeia 3rd edition,in a phosphate buffer medium of pH 6.8, for a volume of 900 ml, at atemperature of 37° C.

Another objective of the present invention is to provide an aqueousliquid suspension of microcapsules of amoxicillin comprising a filmcoating formed of a single layer.

Another objective of the present invention is to provide an aqueousliquid suspension of microcapsules of amoxicillin in which the dissolvedfraction originating from the microcapsules is less than or equal to 15%and preferably 5% of the total weight of amoxicillin present in themicrocapsules.

Another objective of the present invention is to provide an aqueousliquid suspension of microcapsules of amoxicillin in which one part ofthe amoxicillin is in an immediate-release form and the other part ofthe amoxicillin is in a modified-release form (microcapsules).

Another essential objective of the present invention is to provide anaqueous suspension of microcapsules for the modified release ofamoxicillin which makes it possible to release the amoxicillin accordingto a release profile that is not degraded by the ageing of thesuspension.

Another essential objective of the present invention is to provide anaqueous suspension of microcapsules which is made up of individuallycoated particles of amoxicillin and makes it possible to release thelatter according to a prolonged and/or optionally delayed profile suchthat the release half-life t_(1/2) is between 0.5 and 30 hours.

Another objective of the present invention is to propose an oralgalenical form which is liquid and consists of a large number (forexample in the order of several thousands) of microcapsules, thismultiplicity statistically ensuring a good reproducibility of thetransit kinetics of the AP throughout the gastrointestinal tract,thereby improving control of the bioavailability and hence improvingefficacy.

One essential objective of the present invention is to propose an oralliquid galenical form made up of a plurality of coated microcapsuleswhich avoids the use of large amounts of coating agent, the weightfraction of coating agent being comparable to that of the monolithicforms.

Another essential objective of the present invention is to provide amodified-release aqueous suspension in which the amoxicillin is in theform of a plurality of particles individually coated to formmicrocapsules and allowing mixing with other active principles havingdifferent respective release times.

Another essential objective of the present invention is to propose theuse, as a means of treating human or veterinary diseases, of a(preferably aqueous) suspension of microcapsules consisting of particlesof amoxicillin individually coated so as to determine the modifiedrelease of the amoxicillin without the modified-release profile beingaffected by storage of the microcapsules in this liquid form insuspension.

Another essential objective of the present invention is to propose adrug based on a preferably aqueous suspension of microcapsulesconsisting of particles of amoxicillin individually coated so as todetermine the modified release of the amoxicillin without themodified-release profile being affected by storage of the microcapsulesin this liquid form in suspension.

Having set themselves all the above objectives, among others, theinventors have succeeded in developing a multimicrocapsular galenicalsystem in the form of a preferably aqueous suspension for the modifiedrelease of amoxicillin which:

-   -   does not degrade the optionally retarded, modified-release        profile,    -   and is stable, easy to prepare, economic and effective.

To do this the inventors have proposed to:

-   -   select a totally specific coating composition for the        microcapsules,    -   and suspend the microcapsules in a (preferably aqueous) liquid        phase saturated with amoxicillin or capable of being saturated        with amoxicillin on contact with the microcapsules, using an        amount of solvent (preferably water) that is limited but        nevertheless sufficient for the suspension to be easy to        swallow.

Thus the invention which meets the objectives described above, amongothers, relates to a suspension of microcapsules in an aqueous liquidphase, said suspension being intended for oral administration andallowing the modified release of amoxicillin, characterized in that:

-   -   it comprises a plurality of microcapsules each consisting of a        core containing amoxicillin and of a film coating that:        -   is applied to the core,        -   controls the modified release of the amoxicillin,        -   and has a composition corresponding to one of the following            three families A, B and C:            -   Family A            -   1A—at least one film-forming polymer (P1) insoluble in                the tract fluids, present in an amount of 50 to 90 and                preferably of 50 to 80% by dry weight, based on the                total weight of the coating composition, and consisting                of at least one water-insoluble cellulose derivative;            -   2A—at least one nitrogen-containing polymer (P2) present                in an amount of 2 to 25 and preferably of 5 to 15% by                dry weight, based on the total weight of the coating                composition, and consisting of at least one                polyacrylamide and/or poly-N-vinylamide and/or                poly-N-vinyllactam;            -   3A—at least one plasticizer present in an amount of 2 to                20 and preferably of 4 to 15% by dry weight, based on                the total weight of the coating composition, and                consisting of at least one of the following compounds:                glycerol esters, phthalates, citrates, sebacates, cetyl                alcohol esters and castor oil;            -   4A—at least one surfactant and/or lubricant present in                an amount of 2 to 20 and preferably of 4 to 15% by dry                weight, based on the total weight of the coating                composition, and selected from anionic surfactants                and/or non-ionic surfactants and/or lubricants, it being                possible for said agent to comprise only one or a                mixture of the above-mentioned products;            -   Family B            -   1B—at least one hydrophilic polymer carrying groups                ionized at neutral pH and preferably selected from                cellulose derivatives;            -   2B—at least one hydrophobic compound different from A;            -   Family C            -   1C—at least one film-forming polymer insoluble in the                gastrointestinal tract fluids;            -   2C—at least one water-soluble polymer;            -   3C—at least one plasticizer;            -   4C—optionally at least one surfactant/lubricant                preferably selected from the following group of                products:                -   anionic surfactants;                -   and/or non-ionic surfactants,    -   and the liquid phase is saturated or becomes saturated with        amoxicillin on contact with the microcapsules.

In terms of the present disclosure, the expression “microcapsules ofamoxicillin” denotes microcapsules whose core comprises amoxicillin andoptionally at least one other active principle and/or at least oneexcipient.

This suspension according to the invention makes it possible to overcomethe two main obstacles to the production of an aqueous suspension ofmicrocapsules consisting of individually coated microparticles ofamoxicillin and allowing the modified release of the latter, these twoobstacles being as follows:

-   a) limiting the fraction of amoxicillin immediately releasable from    the microcapsules to a value of less than 15% and preferably 5% of    the total weight of amoxicillin used in the microcapsules;-   b) obtaining a modified-release system that is sufficiently robust    to avoid any change or degradation of the release profile of the    amoxicillin during storage of the aqueous suspension.

In one preferred embodiment of the invention, the families A, B and Cfrom which the constituents of the coating composition are selected areas follows:

-   -   Family A    -   1A—ethyl cellulose and/or cellulose acetate;    -   2A—polyacrylamide and/or polyvinylpyrrolidone;    -   3A—castor oil;    -   4A—an alkali metal or alkaline earth metal salt of fatty acids,        stearic and/or oleic acid being preferred, a polyethoxylated        sorbitan ester, a polyethoxylated castor oil derivative, a        stearate, preferably calcium, magnesium, aluminium or zinc        stearate, a stearylfumarate, preferably sodium stearylfumarate,        or glycerol behenate, taken individually or in a mixture with        one another;    -   Family B    -   1B    -   cellulose acetate-phthalate;    -   hydroxypropyl methyl cellulose phthalate;    -   hydroxypropyl methyl cellulose acetate-succinate;    -   (meth)acrylic acid/(meth)acrylic acid alkyl (methyl) ester        copolymer (EUDRAGIT® S or L);    -   and mixtures thereof;    -   2B    -   hydrogenated vegetable waxes (Dynasan® P60, Dynasan® 116);    -   triglycerides (tristearin, tripalmitin, Lubritab®, Cutina HR,        etc.);    -   animal and vegetable fats (beeswax, carnauba wax, etc.);    -   and mixtures thereof.    -   Family C    -   1C    -   water-insoluble cellulose derivatives, ethyl cellulose and/or        cellulose acetate being particularly preferred;    -   acrylic derivatives;    -   polyvinyl acetates;    -   and mixtures thereof;    -   2C    -   water-soluble cellulose derivatives;    -   polyacrylamides;    -   poly-N-vinylamides;    -   poly-N-vinyllactams;    -   polyvinyl alcohols (PVA);    -   polyoxyethylenes (POE);    -   polyvinylpyrrolidones (PVP) (the latter being preferred);    -   and mixtures thereof;    -   3C    -   glycerol and its esters, preferably from the following subgroup:        acetylated glycerides, glycerol monostearate, glyceryl        triacetate and glycerol tributyrate;    -   phthalates, preferably from the following subgroup: dibutyl        phthalate, diethyl phthalate, dimethyl phthalate and dioctyl        phthalate;    -   citrates, preferably from the following subgroup: acetyltributyl        citrate, acetyltriethyl citrate, tributyl citrate and triethyl        citrate;    -   sebacates, preferably from the following subgroup: diethyl        sebacate and dibutyl sebacate;    -   adipates;    -   azelates;    -   benzoates;    -   vegetable oils;    -   fumarates, preferably diethyl fumarate;    -   malates, preferably diethyl malate;    -   oxalates, preferably diethyl oxalate;    -   succinates, preferably dibutyl succinate;    -   butyrates;    -   cetyl alcohol esters;    -   salicylic acid;    -   triacetin;    -   malonates, preferably diethyl malonate;    -   cutin;    -   castor oil (this being particularly preferred);    -   and mixtures thereof;    -   4C    -   alkali metal or alkaline earth metal salts of fatty acids,        stearic and/or oleic acid being preferred;    -   polyethoxylated oils, preferably polyethoxylated hydrogenated        castor oil;    -   polyoxyethylene/polyoxypropylene copolymers;    -   polyethoxylated sorbitan esters;    -   polyethoxylated castor oil derivatives;    -   stearates, preferably calcium, magnesium, aluminium or zinc        stearate;    -   stearylfumarates, preferably sodium stearylfumarate;    -   glycerol behenate;    -   and mixtures thereof.

According to one advantageous modality of the invention in the casewhere the coating contains wax, the latter is selected from compoundswhose melting point T_(f) is ≧40° C. and preferably ≧50° C.

Preferably, the film coating consists of a single layer whose weightrepresents from 1 to 50% and preferably from 5 to 40% of the totalweight of the microcapsules.

According to one preferred characteristic of the invention, the liquidphase is aqueous; even more preferably, it contains at least 20% ofwater and preferably at least 50% by weight of water.

This suspension according to the invention advantageously contains:

-   -   30 to 95% by weight and preferably 60 to 85% by weight of liquid        phase (advantageously water);    -   and 5 to 70% by weight and preferably 15 to 40% by weight of        microcapsules.

Advantageously, the amount of solvent liquid phase (preferably water)for the amoxicillin is such that the proportion of dissolved amoxicillinoriginating from the microcapsules is less than or equal to 15% andpreferably less than or equal to 5% by weight, based on the total weightof amoxicillin contained in the microcapsules.

In a first embodiment of the invention, the liquid phase is at leastpartially and preferably totally saturated with amoxicillin followingthe incorporation of the microcapsules into this liquid phase.

In this embodiment, it is the amoxicillin contained in the microcapsulesthat saturates the liquid phase.

In a second embodiment of the invention, the liquid phase is at leastpartially and preferably totally saturated with amoxicillin by means ofnon-encapsulated amoxicillin prior to the incorporation of themicrocapsules into this liquid phase. This embodiment is of particularvalue for the administration of amoxicillin in that it makes it possibleto combine an immediate-release fraction with a modified-releasefraction.

In practice, this amounts to saturating the liquid phase withamoxicillin before the introduction of the microcapsules into thesuspension, so that the amoxicillin contained in the microcapsules playsno part, or virtually no part, in the saturation of the liquid phase.The diffusion of the amoxicillin contained in the microcapsules istherefore suppressed or virtually suppressed.

According to one preferred characteristic of the invention enabling thisliquid oral formulation to be fully effective, the microcapsules have aparticle size less than or equal to 1000 microns, preferably of between200 and 800 microns and particularly preferably of between 200 and 600microns.

“Particle size” is understood in terms of the invention as meaning thata proportion of at least 75% by weight of microcapsules have a diameterbetween the screen size limits in question.

Again with the aim of improving efficacy, the amount of coating agentfor the microcapsules advantageously represents from 1 to 50% andpreferably 5 to 40% of the weight of the coated microcapsules. Thisadvantageous characteristic is all the . . . to acquire because, due totheir small size, the microcapsules have a large specific surface area,accelerating the release.

To control the in vivo in vitro release of the amoxicillin, it ispreferable according to the invention to use a film coating for themicrocapsules which has a composition belonging to family A or C.

For more detailed qualitative and quantitative information on thiscoating composition of family A, reference may be made to Europeanpatent EP-B-0 709 087, the content of which forms part of the presentdisclosure by way of reference.

Another possible way of defining the liquid suspension according to theinvention consists in considering an in vitro release profile obtainedusing a type II apparatus according to the European Pharmacopoeia 3rdedition, in a phosphate buffer medium of pH 6.8 and at a temperature of37° C., such that:

-   -   the proportion PI of amoxicillin released from the microcapsules        during the first 15 minutes of the dissolution test is such        that:        PI≦15        preferably PI≦5;    -   the amoxicillin remaining in the microcapsules is released over        a period such that the release time of 50% by weight of the        amoxicillin (t_(1/2)) is defined as follows (in hours):        0.5≦t_(1/2)≦30        preferably 0.5≦t_(1/2)≦20.

Still with regard to its in vitro dissolution properties, the suspensionaccording to the invention is characterized in that:

-   -   the initial in vitro release profile Pfi obtained just after        suspension of the microcapsules in the solvent (preferably        aqueous) phase, using a type II apparatus according to the        European Pharmacopoeia 3rd edition, in a phosphate buffer medium        of pH 6.8, for a volume of 900 ml, at a temperature of 37° C.,    -   and the in vitro release profile Pf₁₀ obtained 10 days after        suspension of the microcapsules in the solvent (preferably        aqueous) phase, using a type II apparatus according to the        European Pharmacopoeia 3rd edition, in a phosphate buffer medium        of pH 6.8, at a temperature of 37° C.,        are similar.

The release profiles compared according to the recommendations of TheEuropean Agency for the Evaluation of Medicinal Products (EMEA)—HumanMedicines Evaluation Unit—/Committee for proprietary medicinal products(CPMP)—London, 29 Jul. 1999, CPMP/QWP/604/96: note for guidance onquality of modified release products: A: oral dosage forms, B:transdermal dosage forms—section I (quality)—Annex 3: Similarity factorf₂, produce a value of >50 for the similarity factors f₂ and cantherefore be declared similar.

These advantageous characteristics of the suspension according to theinvention enable amoxicillin to be administered orally withoutdifficulty and without detracting from the modified and optionallydelayed release mode.

According to another of its advantageous physicochemicalcharacteristics, the pH of the liquid suspension according to theinvention can arbitrarily be acidic or neutral.

It may be quite valuable to add at least one rheology modifier to thesuspension. In particular, this can be one or more “viscosifiers”selected . . . those commonly employed in the pharmaceutical industryand especially those disclosed in Handbook of pharmaceuticalexcipients—3rd edition, Am. Pharmaceutical Association, Arthur H. KIBBE,2000, ISBN 0917330-96-X. Europe. 0-85369-381-1. Examples which may bementioned are:

-   -   water-soluble cellulose derivatives (hydroxyethyl cellulose,        hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropyl        methyl cellulose, etc.);    -   polyethylene glycols;    -   alginates and derivatives thereof;    -   carrageenans;    -   agar-agar;    -   gelatin;    -   maltodextrins;    -   polydextrose;    -   guar, carob, acacia, xanthan, gellan and other gums;    -   polyvinyl alcohol;    -   povidone;    -   pectins;    -   silica gel;    -   native and modified starches and derivatives thereof;    -   dextrans;    -   etc.

It can also be advisable to introduce into the suspension at least oneagent for modifying the solubility of the amoxicillin in the solvent(preferably aqueous) liquid phase, for example salts, sugars, glycerol,etc.

For the suspension to have all the qualities of an oral galenical formthat is easy to swallow, stable and palatable, it advantageouslycontains at least one other additive selected from the group comprisingsurfactants, colourants, dispersants, preservatives, taste improvers,flavourings, sweeteners, antioxidants and mixtures thereof.

Examples of these additives which may be mentioned are those commonlyemployed in the pharmaceutical industry and especially those disclosedin Handbook of pharmaceutical excipients—3rd edition, Am. PharmaceuticalAssociation, Arthur H. KIBBE, 2000, ISBN 0917330-96-X. Europe.0-85369-381-1, or, in the case of emulsifiers, those described on page5, lines 14 to 29, of EP-A-0 273 890, or again, in the case ofthickeners, those indicated on page 5, lines 19 and 20, of EP-A-0 601508.

According to another of its features, the present invention relates to adrug, characterized in that it comprises a suspension ofmodified-release microcapsules of amoxicillin, as defined above.

In more concrete terms, the invention further relates to a drug, or moreexactly a galenical pack, characterized in that it comprises a kit forpreparing the suspension as defined above, said kit containing:

-   -   microcapsules in substantially dry form containing amoxicillin        for saturating the liquid phase with amoxicillin once the two        solid and liquid phases have been brought into contact;    -   and/or a mixture of microcapsules in substantially dry form        containing amoxicillin in the dose that is just necessary for        modified release, together with immediate-release uncoated        amoxicillin in a necessary and sufficient amount to saturate the        liquid phase with amoxicillin once the saturation dose of        amoxicillin and the liquid phase have been brought into contact;    -   and the liquid phase and/or at least part of the ingredients        useful for its preparation, and/or the protocol for preparation        of the suspension.

This type of presentation of the drug according to the invention enablespatients easily to prepare the modified-release suspension in a formthat is stable, particularly in terms of modified release, for at leastseveral days. The patient is thus guaranteed to have a drug that is easyto administer orally and perfectly effective from the therapeutic pointof view.

The microcapsules constituting the solid phase of the suspensionaccording to the invention can be prepared by microencapsulationtechniques available to those skilled in the art, the main techniquesbeing summarized in the article by C. DUVERNEY and J. P. BENOIT in“L'actualité chimique”, December 1986. More precisely, the technique inquestion is microencapsulation by film coating, which yieldsindividualized “reservoir” systems as opposed to matrix systems.

For further details, reference may be made to patent EP-B-0 953 359cited above.

To produce the core based on amoxicillin of the microcapsules accordingto the invention, it is advantageous to use, as starting materials,particles of amoxicillin of the desired size. Said particles can becrystals of amoxicillin which are pure and/or have undergone apretreatment by one of the techniques conventionally employed in theart, for example granulation, in the presence of a small amount of atleast one conventional binder and/or an agent for modifying theintrinsic solubility characteristics of the amoxicillin.

The invention will be understood more clearly from the point of view ofits composition, properties and preparation with the aid of the Examplesbelow, given solely by way of illustration, which demonstrate thevariants and the advantages of the invention.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the initial dissolution profile and the dissolution profileafter 12 days' storage of the suspension according to Example 1, in %dissolved as a function of the time in hours.

FIG. 2 shows the initial dissolution-profile and the dissolution profileafter 12 days' storage of the suspension according to Example 2, in %dissolved as a function of the time in hours.

Example 1 Preparation of Microcapsules of Amoxicillin

970 g of amoxicillin trihydrate and 30 g of povidone (Plasdone® K29/32)are first mixed dry in the bowl of a high-shear granulator (Lödige®M5MRK) for 5 minutes. This pulverulent mixture is then granulated withwater (200 g). The granules are dried at 40° C. in a ventilated oven andthen graded on a 500 μm screen. The 200-500 μm fraction is selected bysieving.

700 g of granules obtained above are coated in a GLATT GPCG1 fluidizedair bed apparatus with 107.6 g of ethyl cellulose (Ethocel 7 Premium),35.3 g of povidone (Plasdone® K29/32) and 10.8 g of castor oil dissolvedin an acetone/isopropanol mixture (60/40 w/w).

Preparation of the Suspension:

12.2 g of microcapsules obtained above are mixed dry with 0.3 g ofxanthan gum in a 100 ml glass flask. 87.5 g of purified water are thenadded to the powder mixture. After manual stirring, a suspension isobtained which produces a sediment very slowly. The amoxicillin titre inthe suspension is 0.1 g/ml.

Stability Test:

The suspension prepared above is stored for 12 days at room temperature.After 12 days the suspension is analysed for dissolution using a type IIapparatus according to the European Pharmacopoeia 3rd edition, phosphatebuffer medium of pH 6.8, volume of 900 ml, temperature of 37° C., bladestirring at 100 rpm, UV detection at 272 nm.

The result is shown in FIG. 1 attached.

The profiles are apparently identical: similarity factor f₂ greater than50. The microcapsules remain highly effective in aqueous suspension.

Homogeneity Test:

The above suspension is stirred manually and then six 5 ml samples aretaken with a graduated syringe. The amoxicillin content of each sampleis determined by HPLC and is shown below:

Amoxicillin content for Sample no. 5 ml of suspension (in g) 1 0.51 20.49 3 0.52 4 0.50 5 0.50 6 0.51

It is seen that the samples are very homogeneous and that the dosagecorresponds to the expected value of 0.5 g for 5 ml.

This formulation can therefore be administered without risk ofoverdosing or underdosing.

Example 2 Preparation of Microcapsules of Amoxicillin

970 g of amoxicillin trihydrate and 30 g of povidone (Plasdone® K29/32)are first mixed dry in the bowl of a high-shear granulator (Lödige®M5MRK) for 5 minutes. This pulverulent mixture is then granulated withwater (200 g). The granules are dried at 40° C. in a ventilated oven andthen graded on a 500 μm screen. The 200-500 μm fraction is selected bysieving.

920 g of granules obtained above are coated in a GLATT GPCG1 fluidizedair bed apparatus with 61 g of Aquacoat ECD30, 2.6 g of povidone(Plasdone® K29/32) and 16.4 g of triethyl citrate dispersed in water.

Preparation of the Suspension:

10.9 g of microcapsules obtained above are mixed dry with 0.3 g ofxanthan gum in a 100 ml glass flask. 88.8 g of purified water are thenadded to the powder mixture. After manual stirring, a suspension isobtained which produces a sediment very slowly.

The amoxicillin titre in the suspension is 0.1 g/ml.

Stability Test:

The suspension prepared above is stored for 12 days at room temperature.After 12 days the suspension is analysed for dissolution using a type IIapparatus according to the European Pharmacopoeia 3rd edition, phosphatebuffer medium of pH 6.8, volume of 900 ml, temperature of 37° C., bladestirring at 100 rpm, UV detection at 272 nm.

The result is shown in FIG. 2 attached.

The profiles are apparently identical: similarity factor f₂ greater than50. The microcapsules remain highly effective in aqueous suspension.

KEY TO FIGURES

FIG. 1:

Amoxicilline=amoxicillin

Profil initial=Initial profile

Profil après 12 jours=Profile after 12 days

FIG. 2:

Amoxicilline dissoute=amoxicillin dissolved

profil initial example 2=initial profile of Example 2

profil example 2 après 12 jours=profile of Example 2 after 12 days

Temps (heure)=Time (hours)

1. A suspension of microcapsules in an aqueous liquid phase, saidsuspension being intended for oral administration and allowing themodified release of amoxicillin, wherein said suspension comprises aplurality of microcapsules and an aqueous liquid phase, wherein theaqueous liquid phase is saturated or becomes saturated with activeprinciple(s) on contact with the microcapsules, and wherein eachmicrocapsule comprises (a) a core comprising amoxicillin and (b) a filmcoating that: (i) is applied to the core, (ii) controls the modifiedrelease of the amoxicillin in gastrointestinal tract fluids, and (iii)comprises: (1) at least one film-forming polymer (P1) insoluble ingastrointestinal tract fluids, present in an amount of 50 to 90% by dryweight based on the total weight of the coating composition, and whereinat least one of said at least one film-forming polymer (P1) is awater-insoluble cellulose derivative; (2) at least onenitrogen-containing polymer (P2) present in an amount of 2 to 25% by dryweight based on the total weight of the coating composition, and whereinat least one of said at least one nitrogen-containing polymer (P2) isselected from the group consisting of: polyacrylamide,poly-N-vinylamide, and poly-N-vinyllactam; and (3) at least oneplasticizer present in an amount of 2 to 20% by dry weight based on thetotal weight of the coating composition, and wherein at least one ofsaid at least one plasticizer is selected from the group consisting of:glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters,and castor oil; and wherein the in vitro release profile of thesuspension of microcapsules in an aqueous liquid phase on day ten issimilar to the release profile on day zero, as measured using a type IIapparatus according to the European Pharmacopoeia 3rd edition, in aphosphate buffer medium of pH 6.8, at a temperature of 37° C.
 2. Thesuspension according to claim 1, wherein said the at least onefilm-forming polymer (P1) is selected from the group consisting of ethylcellulose and cellulose acetate; said at least one nitrogen-containingpolymer (P2) is selected from the group consisting of polyacrylamide andpolyvinylpyrrolidone; and said at least one plasticizer is castor oil.3. The suspension according to claim 1, wherein the film coatingconsists of a single layer.
 4. The suspension according to claim 1,wherein said suspension comprises 30 to 95% by weight of liquid phase;and 5 to 70% by weight of microcapsules.
 5. The suspension according toclaim 1, wherein the proportion of dissolved amoxicillin originatingfrom the microcapsules is less than or equal to 15% by weight of thetotal weight of the amoxicillin contained in the microcapsules.
 6. Thesuspension according to claim 1, wherein the amoxicillin contained inthe microcapsules saturates the liquid phase with amoxicillin.
 7. Thesuspension according to claim 1, wherein prior to the incorporation ofthe microcapsules into the aqueous liquid phase, the aqueous liquidphase is at least partially saturated with amoxicillin.
 8. Thesuspension according to claim 1 wherein the microcapsules have aparticle size less than or equal to 1000 microns.
 9. The suspensionaccording to claim 1 wherein from 1 to 50% of the total weight of thecoated microcapsules is film coating.
 10. The suspension according toclaim 1, having an in vitro release profile obtained using a type IIapparatus according to the European Pharmacopoeia 3rd edition, in aphosphate buffer medium of pH 6.8 and at a temperature of 37° C., suchthat: the proportion PI of amoxicillin released during the first 15minutes of the dissolution test is such that: PI≦15%; and the remainingamoxicillin is released over a period such that the release time of 50%by weight of amoxicillin (t_(1/2)) is defined as follows (in hours):0.5≦t_(1/2)≦30.
 11. The suspension according to claim 1 wherein the pHof the suspension is arbitrarily acidic or neutral.
 12. The suspensionaccording to claim 1 wherein the suspension comprises at least onerheology modifier.
 13. The suspension according to claim 1 wherein thesuspension further comprises at least one agent for modifying thesolubility of the amoxicillin in the aqueous liquid phase.
 14. Thesuspension according to claim 1 wherein the suspension further comprisesat least one additive selected from the group consisting of:surfactants, colourants, dispersants, preservatives, taste improvers,flavourings, sweeteners, antioxidants, and mixtures thereof.
 15. A kitfor preparing the suspension according to claim 1, wherein said kitcomprises: microcapsules in substantially dry form comprisingamoxicillin for saturating the liquid phase with amoxicillin once thesolid form and liquid phase have been brought into contact; a mixture ofmicrocapsules in substantially dry form containing amoxicillin in thedose that is just necessary for modified release, wherein eachmicrocapsule comprises (a) a core comprising amoxicillin and (b) a filmcoating that: (i) is applied to the core, (ii) controls the modifiedrelease of the amoxicillin in gastrointestinal tract fluids, and (iii)comprises: (1) at least one film-forming polymer (P1) insoluble ingastrointestinal tract fluids, present in an amount of 50 to 90% by dryweight based on the total weight of the coating composition, and whereinat least one of said at least one film-forming polymer (P1) is awater-insoluble cellulose derivative; (2) at least onenitrogen-containing polymer (P2) present in an amount of 2 to 25% by dryweight based on the total weight of the coating composition, and whereinat least one of said at least one nitrogen-containing polymer (P2) isselected from the group consisting of: polyacrylamide,poly-N-vinylamide, and poly-N-vinyllactam; and (3) at least oneplasticizer present in an amount of 2 to 20% by dry weight based on thetotal weight of the coating composition, and wherein at least one ofsaid at least one plasticizer is selected from the group consisting of:glycerol esters, phthalates, citrates, sebacates, cetyl alcohol esters,and castor oil; and wherein the in vitro release profile of thesuspension of microcapsules in an aqueous liquid phase on day ten issimilar to the release profile on day zero, as measured using a type IIapparatus according to the European Pharmacopoeia 3rd edition, in aphosphate buffer medium of pH 6.8, at a temperature of 37° C.; togetherwith immediate-release uncoated amoxicillin in a necessary andsufficient dose to saturate the liquid phase with amoxicillin once thesaturation dose of amoxicillin and the liquid phase have been broughtinto contact; the liquid phase; at least part of the ingredients usefulfor its preparation; the protocol for preparation of the suspension; orcombinations thereof.
 16. The suspension according to claim 1, whereinsaid film coating further comprises at least one surfactant or lubricantpresent in an amount of 2 to 20% by dry weight based on the total weightof the coating composition, and wherein at least one of said at leastone surfactant or lubricant is selected from the group consisting of:anionic surfactants, non-ionic surfactants, and lubricants, and mixturesthereof.
 17. The suspension according to claim 16, wherein at least oneof the at least one surfactant or lubricant is selected from the groupconsisting of: an alkali metal of fatty acids, an alkaline earth metalsalt of fatty acids, stearic acid, oleic acid, a polyethoxylatedsorbitan ester, a polyethoxylated castor oil derivative, a stearate,stearylfumarate, sodium stearylfumarate, glycerol behenate.
 18. Thesuspension according to claim 4, wherein said suspension comprises 60 to85% by weight of liquid phase.
 19. The suspension according to claim 4,wherein said suspension comprises 15 to 40% by weight of microcapsules.20. The suspension according to claim 1, wherein the proportion ofdissolved amoxicillin originating from the microcapsules is less than orequal to 5% by weight of the total weight of amoxicillin contained inthe microcapsules.
 21. The suspension according to claim 1 wherein themicrocapsules have a particle size of between 200 and 800 microns. 22.The suspension according to claim 1 wherein the microcapsules have aparticle size of between 200 and 600 microns.
 23. The suspensionaccording to claim 1 wherein from 5 to 40% of the total weight of thecoated microcapsules is film coating.
 24. The suspension according toclaim 10, wherein the proportion PI of amoxicillin released during thefirst 15 minutes of the dissolution test is such that: PI≦5% and theremaining amoxicillin is released over a period such that the releasetime of 50% by weight of AP (t_(1/2)) is defined as follows (in hours):0.5≦t_(1/2)≦20.